Common variable immunodeficiency (CVID) is a primary humoral immunodeficiency of uncertain origin. Patients with CVID usually fail to respond to vaccination, but recent evidence observing partial response to mRNA vaccines suggests residual B-cell functionality. In this work, we developed a model to investigate CVID patient´s B-cell function using an in vitro stimulation model, consisting of the isolation of peripheral blood mononuclear cells (PBMCs) from 20 patients with CVID and healthy controls and cultured them with IL-2 and R848. Antibody production was assessed by ELISA and ELISPOT, cytokines were quantified in culture supernatants, and flow cytometry and transcriptomic analyses were performed to characterize cellular and molecular responses. After 10 days of culture, patients failed to sustain antibody production and showed a predominance of IgD-CD27- B cells, while antibodies remained detectable in the culture supernatants. On day 6, the proportion of memory B cells was comparable to healthy controls. The transcriptome analysis showed that patients decreased the expression of genes related to antibody production, adhesion and proinflammatory molecules but increased expression of genes associated with immune inhibitory responses. In the patient’s supernatant, APRIL and IFN-α concentrations were lower but higher BTLA concentration when compared with HC. These findings may suggest new insights into functional impairment after TLR stimulation, which may be relevant to B-cell dysfunction in patients with CVID.